Linked Life Data

1702876

Source:http://linkedlifedata.com/resource/pubmed/id/1702876

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
1991-2-19
pubmed:abstractText
5,10-Dideazatetrahydrofolic acid (DDATHF) is a new potent antitumor agent that specifically inhibits purine biosynthesis, primarily through inhibition of glycinamide ribonucleotide transformylase, the first of the tetrahydrofolate-requiring enzymes in the de novo synthesis pathway. DDATHF has been shown to be an excellent substrate for mouse liver folylpolyglutamate synthetase in vitro, suggesting that intracellular conversion to polyglutamates could play an important role in the action of this antifolate. In this report, metabolic studies of the 6R-diastereomer of DDATHF in the cultured human leukemia cell lines CCRF-CEM and HL-60 are presented. At both 1 and 10 microM (6R)-DDATHF was rapidly converted to polyglutamates in both cell lines. DDATHF(Glu)5 and DDATHF(Glu)6 were the main intracellular metabolites. After incubation in drug-free medium, (6R)-DDATHF polyglutamates were better retained intracellularly with increasing glutamate chain length. (6R)-DDATHF showed reduced cytotoxicity toward a folylpolyglutamate synthetase-deficient cell line, CCRF-CEM30/6 related to a dramatically diminished accumulation of polyglutamates. The activity of (6R)-DDATHF in CCRF-CEM30/6 cells was decreased after both short and prolonged exposures. These results suggest that polyglutamylation of (6R)-DDATHF not only represents a mechanism for trapping the drug inside the cells but also produces a more potent inhibitor of the target enzyme.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0026-895X
pubmed:author
pubmed:issnType
Print
pubmed:volume
39
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
85-9
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed:year
1991
pubmed:articleTitle
Intracellular metabolism of 5,10-dideazatetrahydrofolic acid in human leukemia cell lines.
pubmed:affiliation
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't